The present invention relates to bis-basic compounds having tryptase-inhibiting activity, processes for preparing such compounds, their therapeutic use in the treatment of disease, and pharmaceutical compositions comprising such compounds.
Tryptase inhibitors may be used in the production of pharmaceutical compositions which are used to prevent and/or treat inflammatory and/or allergic conditions.
The object of the present invention is therefore to provide new compounds that have a tryptase-inhibiting activity and may be used to prevent and treat conditions in which tryptase inhibitors may have a therapeutic value.
The compounds according to the invention are bis-basic compounds of general formula (I)
B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94Axe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94B2 xe2x80x83xe2x80x83(I)
wherein
B1 and B2 which may be identical or different denote xe2x80x94C(xe2x95x90NR1)xe2x80x94NR1xe2x80x2H, xe2x80x94CH2NH2, xe2x80x94CH2CH2NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2;
R1 and R1xe2x80x2 which may be identical or different denote hydrogen, OH, xe2x80x94COR2 or xe2x80x94COOR2;
R2 denotes hydrogen, C1-C18-alkyl, aryl or aryl-C1-C6-alkyl;
Ar1, Ar2, Ar3, Ar4 and aryl which may be identical or different denote C6-C10-aryl, which may optionally be mono- to tetrasubstituted by one or more groups selected from among C3-C10-cycloalkyl, F, Cl , Br, I, OH, OR3, SR3, NR3R4, COOR3, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, whilst in the substituents C1-C6-alkyl and C2-C6-alkenyl one or more hydrogen atoms may optionally be replaced by F or OR3, or
xe2x80x83a 5-10-membered mono- or bicyclic heteroaryl ring, wherein up to three carbon atoms may be replaced by one or more heteroatoms selected from among oxygen, nitrogen and sulphur and which may optionally be mono- to tetrasubstituted by one or more groups selected from among C1-C10-cycloalkyl, F, Cl, Br, I, OH, OR3, SR3, NR3R4, COOR3, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, whilst in the substituents C1-C6-alkyl and C2-C6-alkenyl one or more hydrogen atoms may optionally be replaced by F or OR3;
R3 and R4 which may be identical or different denote hydrogen or a group selected from among C1-C6-alkyl and C3-C6-cycloalkyl wherein one or more hydrogen atoms may optionally be replaced by F;
X1, X2, X3 and X4 which may be identical or different denote a bridge selected from among xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nOxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94, xe2x80x94(CH2)nNR3xe2x80x94 and xe2x80x94(CH2)nN+R3R4xe2x80x94 where n=1 or 2;
A denotes a group selected from among C2-C16-alkylene and C2-C16-alkenylene, wherein optionally one or more hydrogen atoms may be replaced by one or more groups selected from among F, R3, OR3 and COOR3, or A denotes C2-C16-alkynylene, or
A denotes xe2x80x94(CH2)lxe2x80x94Dxe2x80x94(CH2)mxe2x80x94, whilst in the alkylene groups xe2x80x94(CH2)lxe2x80x94 and xe2x80x94(CH2)mxe2x80x94 one or two hydrogen atoms may optionally be replaced by C1-C6-alkyl and wherein
D denotes aryl or C3-C10-cycloalkyl wherein one or more hydrogen atoms may optionally be replaced by one or more groups selected from among F, R3 and OR3 and l and m, which may be identical or different, denote 0, 1, 2, 3 or 4,
or
D denotes xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR3xe2x80x94 and l and m, which may be identical or different, denote 2, 3 or 4;
or
A denotes xe2x80x94G1xe2x80x94(CH2)rxe2x80x94G2xe2x80x94, if X2 or X3 denote xe2x80x94(CH2)nxe2x80x94, A may also denote xe2x80x94E1xe2x80x94(CH2)rxe2x80x94G1xe2x80x94 or xe2x80x94E1xe2x80x94(CH2)rxe2x80x94E2xe2x80x94,
wherein
r denotes the number 0, 1, 2, 3, 4, 5 or 6,
G1 and G2 which may be identical or different denote a single bond or C3-C10-cycloalkyl, but if r=0 or r=1 G1 and G2 cannot simultaneously represent a single bond;
E1 and E2 which may be identical or different denote C3-C10-aza-cycloalkyl which contains one or two nitrogen atoms, wherein at least one N-atom is bound to X2 or X3=(CH2)n,
optionally in the form of their racemates, enantiomers, diastereomers, tautomers and mixtures thereof, and optionally the pharmacologically harmless acid addition salts thereof.
Preferred compounds of general formula (I) are those wherein
B1 and B2 which may be identical or different denote xe2x80x94C(xe2x95x90NR1)xe2x80x94NR1xe2x80x2H, xe2x80x94CH2NH2, xe2x80x94CH2CH2NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2;
R1 and R1xe2x80x2 which may be identical or different denote hydrogen, OH, xe2x80x94COR2 or xe2x80x94COOR2;
R2 denotes hydrogen, C1-C14-alkyl, aryl or aryl-C1-C6-alkyl;
Ar1, Ar2, Ar3, Ar4 and aryl which may be identical or different, denote C6-C10-aryl which may optionally be mono- to tetrasubstituted by one or more groups selected from among C3-C8-cycloalkyl, F, Cl, Br, I, OH, OR3, NR3R4, COOR3, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, whilst in the substituents C1-C6-alkyl and C2-C6-alkenyl one or more hydrogen atoms may optionally be replaced by F, or
xe2x80x83a 5-10-membered mono- or bicyclic heteroaryl ring, wherein up to three carbon atoms may be replaced by one or more heteroatoms selected from among oxygen, nitrogen and sulphur and which may optionally be mono- to tetrasubstituted by one or more groups selected from among F, OR3, COOR3 or C1-C6-alkyl, wherein in the substituent C1-C6-alkyl one or more hydrogen atoms may optionally be replaced by F;
R3 and R4 which may be identical or different denote hydrogen or a group selected from among C1-C6-alkyl and C3-C6-cycloalkyl wherein one or more hydrogen atoms may optionally be replaced by F;
X1, X2, X3 and X4 which may be identical or different denote a bridge selected from among xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nOxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94, xe2x80x94(CH2)nNR3xe2x80x94 and xe2x80x94(CH2)nN+R3R4xe2x80x94 where n=1 or 2;
A denotes a group selected from among C2-C14-alkylene and C2-C10-alkenylene, wherein optionally one or more hydrogen atoms may be replaced by one or more groups selected from among F, R3, OR3 and COOR3, or A denotes C2-C10-alkynylene, or
A denotes xe2x80x94(CH2)lxe2x80x94Dxe2x80x94(CH2)mxe2x80x94, whilst in the alkylene groups xe2x80x94(CH2)lxe2x80x94 and xe2x80x94(CH2)mxe2x80x94 one or two hydrogen atoms may optionally be replaced by C1-C6-alkyl and wherein
D denotes aryl or C3-C8-cycloalkyl wherein one or more hydrogen atoms may optionally be replaced by one or more groups selected from among F, R3 and OR3 and l and m, which may be identical or different, denote 0, 1, 2, 3 or 4,
or
D denotes xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR3xe2x80x94 and l and m, which may be identical or different, denote 2, 3 or 4;
or
A denotes xe2x80x94G1xe2x80x94(CH2)rxe2x80x94G2xe2x80x94,
if X2 or X3 represents xe2x80x94(CH2)nxe2x80x94, A also denotes xe2x80x94E1xe2x80x94(CH2)rxe2x80x94G1xe2x80x94 or xe2x80x94E1xe2x80x94(CH2)rxe2x80x94E2xe2x80x94,
wherein
r denotes the number 0, 1, 2, 3, 4, 5 or 6,
G1 and G2 which may be identical or different denote a single bond or C3-C8-cycloalkyl, but if r=0 or r=1 G1 and G2 cannot simultaneously represent a single bond;
E1 and E2 which may be identical or different denote C3-C8-aza-cycloalkyl which contains one or two nitrogen atoms, wherein at least one N-atom is bound to X2 or X3=(CH2)n,
optionally in the form of their racemates, enantiomers, diastereomers, tautomers and mixtures thereof, and optionally the pharmacologically harmless acid addition salts thereof.
Particularly preferred are compounds of general formula (I), wherein
B1 and B2 which may be identical or different denote xe2x80x94C(xe2x95x90NR1)xe2x80x94NR1xe2x80x2H, xe2x80x94CH2NH2, xe2x80x94CH2CH2NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2;
R1 and R1xe2x80x2 which may be identical or different denote hydrogen, OH, xe2x80x94COR2 or xe2x80x94COOR2;
R2 denotes hydrogen, C1-C10-alkyl or aryl-C1-C4-alkyl;
Ar1, Ar2, Ar3, Ar4 and aryl which may be identical or different, denote phenyl or naphthyl which may optionally be mono-, dixe2x80x94 or trisubstituted by one or more groups selected from among F, OR3, NR3R4, COOR3 or C1-C6-alkyl, wherein in the substituent C1-C6-alkyl one or more hydrogen atoms may optionally be replaced by F or OR3;
R3 and R4 which may be identical or different denote hydrogen or a group selected from among cyclopropyl, cyclopentyl, cyclohexyl and C1-C4-alkyl wherein one or more hydrogen atoms may optionally be replaced by F;
X1, X2, X3 and X4 which may be identical or different denote a bridge selected from among xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nOxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94, xe2x80x94(CH2)nNR3xe2x80x94 and xe2x80x94(CH2)nN+R3R4xe2x80x94 where n=1 or 2, preferably where n=1;
A denotes C2-C12-alkylene wherein optionally one or more hydrogen atoms may be replaced by one or more groups selected from among F, OR3 and COOR3, or
A denotes xe2x80x94(CH2)lxe2x80x94Dxe2x80x94(CH2)mxe2x80x94, whilst in the alkylene groups xe2x80x94(CH2)lxe2x80x94 and xe2x80x94(CH2)mxe2x80x94 one or two hydrogen atoms may optionally be replaced by a C1-C4 group and wherein
D denotes a group selected from among phenyl, cyclopentyl and cyclohexyl wherein one or more hydrogen atoms may optionally be replaced by one or more groups selected from among F, R3 and OR3 and l and m, which may be identical or different, denote 0, 1, 2, 3 or 4, or
D denotes xe2x80x94Oxe2x80x94 or xe2x80x94NR3xe2x80x94 and l and m, which may be identical or different, denote 2, 3 or 4;
or
A denotes xe2x80x94G1xe2x80x94(CH2)rxe2x80x94G2xe2x80x94,
if X2 or X3 represents xe2x80x94(CH2)nxe2x80x94, A also denotes xe2x80x94E1xe2x80x94(CH2)rxe2x80x94G1xe2x80x94 or xe2x80x94E1xe2x80x94(CH2)rxe2x80x94E2xe2x80x94,
wherein
r denotes the number 0, 1, 2, 3 or 4,
G1 and G2 which may be identical or different denote a single bond, cyclopentyl, cyclohexyl or cycloheptyl, if r=0 or r=1 G1 and G2 cannot simultaneously represent a single bond;
E1 and E2 which may be identical or different denote a group selected from among pyrrolidine, imidazolidine, piperidine and piperazine, wherein at least one N-atom is bound to X2 or X3=(CH2)n,
optionally in the form of their racemates, enantiomers, diastereomers, tautomers and mixtures thereof, and optionally the pharmacologically harmless acid addition salts thereof. Of particular importance according to the invention are compounds of general formula (I)
wherein
B1 and B2 which may be identical or different denote xe2x80x94C(xe2x95x90NR1)xe2x80x94NR1xe2x80x2H, xe2x80x94CH2NH2, xe2x80x94CH2CH2NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2;
R1 and R1xe2x80x2 which may be identical or different denote hydrogen, OH, xe2x80x94COR2 or xe2x80x94COOR2, preferably hydrogen or OH,
R2 denotes hydrogen, C1-C6-alkyl or benzyl;
Ar1, Ar2, Ar3 and Ar4 which may be identical or different, denote phenyl which may optionally be mono-, dixe2x80x94 or trisubstituted by one or more groups selected from among F, OR3, NR3R4, COOR3 or C1-C4-alkyl, wherein in the substituent C1-C4-alkyl one or more hydrogen atoms may optionally be replaced by F;
R3 and R4 which may be identical or different denote hydrogen or a group selected from among cyclopropyl, cyclopentyl, cyclohexyl and C1-C4-alkyl, wherein one or more hydrogen atoms may optionally be replaced by F;
X1, X2, X3 and X4 which may be identical or different denote a bridge selected from among xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nOxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94, xe2x80x94(CH2)nNR3xe2x80x94 and xe2x80x94(CH2)nN+R3R4xe2x80x94 where n=1 or 2, preferably where n=1; or
A denotes C2-C12-alkylene wherein one or more hydrogen atoms may optionally be replaced by one or more groups selected from among F, OR3 and COOR3, or
A denotes xe2x80x94(CH2)lxe2x80x94Dxe2x80x94(CH2)mxe2x80x94, whilst in the alkylene groups xe2x80x94(CH2)lxe2x80x94 and xe2x80x94(CH2)mxe2x80x94 one or two hydrogen atoms may optionally be replaced by a methyl group and wherein
D denotes a group selected from among phenyl and cyclohexyl wherein optionally one or more hydrogen atoms may be replaced by one or more groups selected from among F, R3 and OR3 and l and m, which may be identical or different, denote 0, 1, 2 or 3,
or
D denotes xe2x80x94Oxe2x80x94 and l and m, which may be identical or different, denote 2 or 3;
or
A denotes xe2x80x94G1xe2x80x94(CH2)rxe2x80x94G2xe2x80x94,
if X2 or X3 represents xe2x80x94(CH2)nxe2x80x94 A also denotes xe2x80x94E1xe2x80x94(CH2)rxe2x80x94G1xe2x80x94 or xe2x80x94E1xe2x80x94(CH2)rxe2x80x94E2xe2x80x94,
wherein
r denotes the number 0, 1, 2 or 3,
G1 and G2 which may be identical or different denote a single bond, cyclopentyl or cyclohexyl, but if r=0 or r=1 G1 and G2 cannot simultaneously represent a single bond;
E1 and E2 which may be identical or different denote piperidine or piperazine, wherein at least one N-atom is bound to X2 or X3=(CH2)n,
optionally in the form of their racemates, enantiomers, diastereomers, tautomers and mixtures thereof, and optionally the pharmacologically harmless acid addition salts thereof.
Also of significance according to the invention are compounds of general formula (I),
wherein
B1 and B2 which may be identical or different denote xe2x80x94C(xe2x95x90NR1)xe2x80x94NH2, xe2x80x94CH2NH2 or xe2x80x94CH2CH2NH2;
R1 denotes hydrogen, OH, xe2x80x94COR2 or xe2x80x94COOR2, preferably hydrogen or OH,
R2 denotes hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl or benzyl;
Ar1, Ar2, Ar3 and Ar4, which may be identical or different, denote phenyl;
X1, X2, X3 and X4 which may be identical or different denote a bridge selected from among xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nOxe2x80x94, xe2x80x94(CH2)nNHxe2x80x94, xe2x80x94(CH2)nNMexe2x80x94, xe2x80x94(CH2)nNEtxe2x80x94, xe2x80x94(CH2)nNpropxe2x80x94, xe2x80x94(CH2)nNcyclopropyxe2x80x94, xe2x80x94(CH2)nNBuxe2x80x94 and xe2x80x94(CH2)nN+(Me)2 where n=1;
A denotes C2-C12-alkylene which may optionally be substituted by a group selected from among OH, COOH and COOMe, or
xe2x80x83xe2x80x94(CH2)lxe2x80x94Dxe2x80x94(CH2)mxe2x80x94, whilst in the alkylene groups xe2x80x94(CH2)lxe2x80x94 and xe2x80x94(CH2)mxe2x80x94 one or two hydrogen atoms may optionally be replaced by methyl and wherein
D denotes phenyl or cyclohexyl which may optionally be substituted by methyl and l and m, which may be identical or different, denote 0, 1, 2 or 3,
xe2x80x83or
D denotes xe2x80x94Oxe2x80x94 and l and m, which may be identical or different, represent 2 or 3;
or
A denotes xe2x80x94G1xe2x80x94(CH2)rxe2x80x94G2xe2x80x94,
if X2 or X3 denotes xe2x80x94(CH2)nxe2x80x94 A may also denote xe2x80x94E1xe2x80x94(CH2)rxe2x80x94G1xe2x80x94 or xe2x80x94E1xe2x80x94(CH2)rxe2x80x94E2xe2x80x94,
wherein
r denotes the number 0, 1, 2 or 3,
G1 and G2 which may be identical or different denote a single bond or cyclohexyl, but if r=0 or r=1 G1 and G2 cannot simultaneously represent a single bond;
E1 and E2 which may be identical or different denote piperidine or piperazine, wherein at least one N-atom is bound to X2 or X3=(CH2)n,
optionally in the form of their racemates, enantiomers, diastereomers, tautomers and mixtures thereof, and optionally the pharmacologically harmless acid addition salts thereof.
Also preferred are compounds of general formula (IA) 
wherein B1, B2, A, X2 and X3 have the meanings given hereinbefore and hereinafter, optionally in the form of their racemates, enantiomers, diastereomers, tautomers and mixtures thereof, and optionally the pharmacologically harmless acid addition salts thereof.
Of particular importance are the compounds of general formula (I) or (IA) according to the invention wherein
the grouping B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94 denotes a group selected from among 
the grouping xe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94B2 denotes a group selected from among 
B1 and B2 which may be identical or different denote xe2x80x94C(xe2x95x90NR1)xe2x80x94NR1xe2x80x2H, xe2x80x94CH2NH2, xe2x80x94CH2CH2NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2;
R1 and R1xe2x80x2 which may be identical or different denote hydrogen or OH, preferably hydrogen;
A denotes a bridging group which is selected from among (viii) C4-C10-alkylene which may optionally be substituted by COOH, 
xe2x80x83or
A may also denote 
xe2x80x83if the grouping B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94 represents the group 
xe2x80x83and the grouping xe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94B2 represents the group 
xe2x80x83or
A may also denote 
xe2x80x83if the grouping of the two groups B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94 and xe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94B2 represents the group (i) or (ixe2x80x2) which is bound directly to the piperazine-nitrogen of the group A,
optionally in the form of their racemates, enantiomers, diastereomers, tautomers and mixtures thereof, and optionally the pharmacologically harmless acid addition salts thereof.
Also of special importance are the compounds of general formula (I) according to the invention wherein
the grouping B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94 denotes a group selected from among 
the grouping xe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94B2 denotes a group selected from among 
wherein
B1 and B2 which may be identical or different denote xe2x80x94C(xe2x95x90NR1)xe2x80x94NR1xe2x80x2H or xe2x80x94CH2NH2,
R1 and R1xe2x80x2 which may be identical or different denote hydrogen or OH, preferably hydrogen;
A denotes a bridging group which is selected from among (viii) C4-C10-alkylene, 
xe2x80x83or
A may also denote 
xe2x80x83if the grouping B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94 denotes the group (i) and the grouping xe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94B2 denotes the group (ixe2x80x2),
optionally in the form of their racemates, enantiomers, diastereomers, tautomers and mixtures thereof, and optionally the pharmacologically harmless acid addition salts thereof.
Particularly preferred are the compounds of general formula (IA1) 
wherein B1, B2, A, X2 and X3 have the meanings given hereinbefore and hereinafter, optionally in the form of their racemates, enantiomers, diastereomers, tautomers and mixtures thereof, and optionally the pharmacologically harmless acid addition salts thereof.
Particularly preferred are the compounds of general formula (I), (IA) or (IA1), wherein xe2x80x94X2xe2x80x94Axe2x80x94X3xe2x80x94 denotes a group of the formula 
Compounds of general formula (I) wherein B1 and B2 which may be identical or different denote xe2x80x94C(xe2x95x90NR1)xe2x80x94NR1xe2x80x2H are so-called prodrugs if neither R1 nor R1xe2x80x2 denotes hydrogen. After being taken by the patient these prodrugs can be converted by the body, on the basis of a functionality which can be cleaved in vivo, into the therapeutically active compounds of general formula (I) wherein B1 and B2 which may be identical or different denote xe2x80x94C(xe2x95x90NH)NH2.
The term alkyl groups (including those which are part of other groups) denotes branched and unbranched alkyl groups with 1 to 18 carbon atoms, preferably 1-14, most preferably 1-10 carbon atoms, unless otherwise stated. Examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl, etc. Unless otherwise stated, the above terms propyl, butyl, pentyl, hexyl, heptyl and octyl, etc., also include all the possible isomeric forms. For example, the term propyl also includes the two isomeric groups n-propyl and iso-propyl, the term butyl includes n-butyl, iso-butyl, sec. butyl and tert.-butyl, the term pentyl includes iso-pentyl, neopentyl, etc. In some cases common abbreviations are also used to denote the abovementioned alkyl groups, such as Me for methyl, Et for ethyl etc.
Examples of alkylene groups are branched and unbranched alkylene bridges having 1 to 18 carbon atoms, preferably 1-14 carbon atoms, most preferably 1-10 carbon atoms. These include, for example: methylene, ethylene, propylene, butylene, etc. Unless otherwise stated, the above terms propylene, butylene, etc. also include all the possible isomeric forms. For example, the term propylene includes the two isomeric bridges n-propylene and dimethylmethylene, the term butylene includes n-butylene, 1-methylpropylene, 2-methylpropylene, 1.1-dimethylethylene, 1.2-dimethylethylene etc.
The term alkenyl groups (including those which are part of other groups) denotes branched and unbranched alkenyl groups having 2 to 16 carbon atoms, preferably 2 to 10 carbon atoms, most preferably 2 to 6 carbon atoms, if they contain at least one double bond, for example the abovementioned alkyl groups as well, provided that they contain at least one double bond, such as for example vinyl (provided that no unstable enamines or enolethers are formed), propenyl, iso-propenyl, butenyl, pentenyl, hexenyl.
The term alkynyl groups (including those which are part of other groups) denotes branched and unbranched alkenyl groups having 2 to 16 carbon atoms, preferably 2 to 10 carbon atoms, most preferably 2 to 6 carbon atoms, provided that they have at least one triple bond, for example ethynyl, propargyl, butynyl, pentynyl, hexynyl.
In the abovementioned alkyl groups, alkylene groups and alkenyl groups, one or more hydrogen atoms may optionally be substituted by the groups specified in the definitions. By the phrase xe2x80x9cseveral substituted hydrogen atomsxe2x80x9d is meant the substitution of at least 2 hydrogen atoms. When the substituent is fluorine all the hydrogen atoms of the alkyl, alkylene and alkenyl groups may optionally be replaced.
Examples of cycloalkyl groups with 3-10 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl, which may also be substituted by branched or unbranched alkyl having 1 to 4 carbon atoms, hydroxy and/or halogen or as hereinbefore defined.
In the abovementioned cycloalkyl groups one or more hydrogen atoms may optionally be substituted by the groups mentioned in the definitions. By the phrase xe2x80x9cseveral substituted hydrogen atomsxe2x80x9d is meant the substitution of at least 2 hydrogen atoms. When the substituent is fluorine all the hydrogen atoms of the cycloalkyl group may optionally be replaced.
Fluorine, chlorine, bromine or iodine is generally referred to as halogen.
The term C3-C10-aza-cycloalkyl groups denotes 3- to 10-membered cycloalkyl groups which contain one or two nitrogen atoms. These include, for example, pyrrolidine, imidazolidine, piperidine, piperazine, azepan, diazepans, etc., each of which, unless otherwise specified, may also be substituted by branched or unbranched alkyl with 1 to 4 carbon atoms, hydroxy and/or halogen or as hereinbefore defined.
Examples of 5-10-membered mono- or bicyclic heteroaryl rings in which up to three carbon atoms may be replaced by one or more heteroatoms selected from among oxygen, nitrogen or sulphur include for example furan, thiophene, pyrrole, pyrazole, imidazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, wherein each of the abovementioned heterocycles may optionally also be condensed onto a benzene ring and wherein these heterocycles may be substituted as specified in the definitions.
The term C6-C10-aryl denotes an aromatic ring system with 6 to 10 carbon atoms, which, unless otherwise stated, may for example carry one or more of the following substituents: C1-C6-alkyl, C1-C6-alkyloxy, halogen, hydroxy, mercapto, amino, alkylamino, dialkylamino, CF3, cyano, nitro, xe2x80x94CHO, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-C6-alkyl, xe2x80x94Sxe2x80x94C1-C6-alkyl. The preferred aryl group is phenyl.
xe2x80x9cxe2x95x90Oxe2x80x9d denotes an oxygen atom linked via a double bond.
In the abovementioned definitions, unless otherwise specified, all the definitions given for the groups xe2x80x94Ar1xe2x80x94, xe2x80x94Ar2xe2x80x94, xe2x80x94Ar3xe2x80x94 and xe2x80x94Ar4xe2x80x94 should be regarded as two-bonded groups which may be linked to the two adjacent functions in three possible substitution patterns (ortho, meta and para). Meta- and para-substitution are preferred.
In the abovementioned definitions, unless otherwise specified, all the definitions given for the groups xe2x80x94X1xe2x80x94, xe2x80x94X2xe2x80x94, xe2x80x94Axe2x80x94, xe2x80x94X3xe2x80x94 and xe2x80x94X4xe2x80x94 should be regarded as two-bonded groups which may be linked to the two adjacent functions in two possible orientations. Preferably, xe2x80x94X1xe2x80x94 denotes xe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94Sxe2x80x94(CH2)nxe2x80x94 or xe2x80x94NR3xe2x80x94(CH2)nxe2x80x94 particularly xe2x80x94Oxe2x80x94CH2xe2x80x94; and xe2x80x94X4xe2x80x94 denotes xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94or xe2x80x94(CH2)xe2x80x94NR3xe2x80x94n, particularly xe2x80x94CH2xe2x80x94Oxe2x80x94.
According to another aspect, the present invention relates to the use of the above-defined compounds of general formula (I) as pharmaceutical compositions. In particular, the present invention relates to the use of the compounds of general formula (I) for preparing a pharmaceutical composition for the prevention and/or treatment of diseases in which tryptase inhibitors may have a therapeutic benefit.
It is preferred according to the invention to use compounds of general formula (I) for the purpose mentioned above, for preparing a pharmaceutical composition for the prevention and/or treatment of inflammatory and/or allergic diseases.
It is particularly preferable to use the compounds of general formula (I) as mentioned above for preparing a pharmaceutical composition for the prevention and/or treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, allergic otitis, allergic gastro-intestinal disorders, Crohn""s disease, ulcerative colitis, anaphylactic shock, septic shock, shock lung (ARDS) and arthritis.
It is also advantageous to use the compounds of general formula (I) as mentioned above for preparing a pharmaceutical composition for the prevention and/or treatment of fibroses such as lung fibrosis, fibrosing alveolitis and scarring, collagenoses such as lupus erythematodes and sclerodermia as well as arteriosclerosis, psoriasis and neoplasm.
One possible method of obtaining the compounds of general formula (I) according to the invention with the aid of and using conventional chemical methods of synthesis is diagrammatically shown hereinafter.
Method A
In order to prepare compounds of general formula (I)
B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94Axe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94B2 xe2x80x83xe2x80x83(I)
wherein B1 and B2 denote xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, imidoesters of general formula (II)
ROxe2x80x94C(xe2x95x90NH)xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94Axe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94C(xe2x95x90NH)xe2x80x94OR xe2x80x83xe2x80x83(II)
wherein R denotes C1-C6-alkyl, are reacted with ammonia.
The reaction is preferably carried out in an organic solvent at temperatures between about 0xc2x0 C. and the boiling temperature of the reaction mixture, preferably between ambient temperature and about 100xc2x0 C. or the boiling temperature of the solvent used, if this is lower. Suitable solvents are polar organic solvents, preferably alcohols, most preferably methanol, ethanol or propanols. If the starting materials are sufficiently acid-stable the reaction may take place via the corresponding acid imide chlorides instead of via the imidoesters.
Method B1
In order to prepare compounds of general formula (I)
B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94Axe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94B2 xe2x80x83xe2x80x83(I)
wherein B1 and B2 denote xe2x80x94C(xe2x95x90NOH)xe2x80x94NH2, compounds of general formula (III)
NCxe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94Axe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94CN xe2x80x83xe2x80x83(III)
are treated with hydroxylamine in the presence of carbonates or alkoxides of the alkali or alkaline earth metals in solvents such as methanol, ethanol, n-propanol or isopropanol, possibly in admixture with dioxan or tetrahydrofuran. The alkoxides may be prepared from the alkali metals or metal hydrides and the corresponding alcohol. The reaction is preferably carried out at 20-100xc2x0 C., most preferably at the boiling temperature of the solvent used.
Method B2 
In order to prepare compounds of general formula (I)
B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94Axe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94B2 xe2x80x83xe2x80x83(I)
wherein B1 and B2 denote xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, amidoximes of general formula (I) wherein B1 and B2 denote xe2x80x94C(xe2x95x90NOH)xe2x80x94NH2 are reduced.
Catalytic hydrogenation is suitable for the reduction, particularly with Raney nickel, palladium or platinum in a lower alcohol, e.g. methanol, ethanol or propanols. Appropriately the amidoxime is dissolved in a polar solvent, e.g. methanol, ethanol, propanols, tetrahydrofuran or dimethylformamide, with the addition of the calculated amount of the acid whose salt is desired as the end product, and hydrogenated at ambient temperature under gentle pressure from 1 bar, e.g. at 5 bar, until the uptake of hydrogen has ceased.
Method C
In order to prepare compounds of general formula (I)
B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94Axe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94B2 xe2x80x83xe2x80x83(I)
wherein B1 and B2 denote xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, compounds of general formula (III)
NCxe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94Axe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94CN xe2x80x83xe2x80x83(Ill)
are reacted with Li-hexamethyldisilazane. Suitable solvents for the reaction are nonpolar and polar aprotic solvents such as for example toluene, ether or tetrahydrofuran at temperatures of xe2x88x9280xc2x0 C. to 120xc2x0 C. To cleave the silyl groups inorganic and organic acids are used such as HCl, HBr, H2SO4, sulphonic acids such as p-toluenesulphonic acid, benzenesulphonic acid or methanesulphonic acid, carboxylic acids such as formic acid, acetic acid or trifluoroacetic acid at temperatures of 0xc2x0 C. to 100xc2x0 C.
Method D
In order to prepare compounds of general formula (I)
B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94Axe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94B2 xe2x80x83xe2x80x83(I)
wherein B1 and B2 may have the meanings given hereinbefore, compounds of general formula (IV and (V)
PG-B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94CHOxe2x80x83xe2x80x83(IV)
OHCxe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94B2-PGxe2x80x83xe2x80x83(V)
wherein PG may denote a protecting group suitable for protecting amines, which may also be present twice, are reacted with a diamine with subsequent reduction of the Cxe2x95x90Nxe2x80x94 double bonds thus formed. Suitable amino protecting groups PG which may be mentioned here include for example alkoxycarbonyl, particularly tert-butyloxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl etc. For the reaction, aldehydes of formula (IV) and (V) are reacted with diamines in aprotic solvents such as toluene, dichloromethane, ethyl acetate, ether, tetrahydrofuran etc. at temperatures of xe2x88x9280xc2x0 C. to 120xc2x0 C. The subsequent reduction may be carried out with complex hydrides such as for example LiAlH4, Li-alkoxyhydrides, NaBH4, NaBHCN3, NaBH(OAc)3, etc.
For the reaction with primary amines NaBH4 is preferably used, while for secondary amines NaBH(OAc)3 is preferred. The solvents used may be polar solvents such as DMF, alcohols such as methanol, ethanol, propanols etc. and water. The temperature is kept in a range from xe2x88x9230xc2x0 C. to 100xc2x0 C. For cleaving the hydride complexes, organic and inorganic acids are used, such as HCl, HBr, H2SO4, formic acid, acetic acid, sulphonic acids such as p-toluenesulphonic acid, benzenesulphonic acid or methanesulphonic acid in polar solvents such as ethyl acetate, methanol, ethanol, propanols, water, DMF, acetonitrile. Finally, the protecting groups are cleaved, particularly with inorganic or organic acids or by hydrogenolysis or using other methods known from the prior art which are conventionally used for cleaving specific protecting groups.
Method E
In order to prepare compounds of general formula (I)
B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94Axe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94B2 xe2x80x83xe2x80x83(I)
wherein B1 and B2 may have the meanings given hereinbefore, compounds of general formula (VI) and (VII)
PGxe2x80x94B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94CH2Yxe2x80x83xe2x80x83(VI)
YCH2xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94Bxe2x80x94PGxe2x80x83xe2x80x83(VII);
wherein PG may denote a protecting group used to protect amines, which may also be present twice and
Y denotes fluorine, chlorine, bromine or iodine or a C1-C4-alkylxe2x80x94 or an arylsulphonate group
are reacted with a diamine or a dialcohol. Suitable amino protecting groups PG which may be mentioned here include for example alkoxycarbonyl, particularly tert-butyloxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl etc.
The reaction is carried out with basic adjuvants such as for example alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal carbonates, C1-C4-alkali metal alkoxides in solvents which are inert under the reaction conditions used, such as formamidesxe2x80x94preferably dimethylformamide (DMF)xe2x80x94, C1-C4-alkyl esters of carboxylic acidsxe2x80x94preferably ethyl acetate or ethyl formatexe2x80x94, aromatic or aliphatic hydrocarbonsxe2x80x94preferably toluenexe2x80x94or in branched or unbranched C1-C4-alcohols.
In the final reaction step, the protecting groups are cleaved, particularly with inorganic or organic acids or by hydrogenolysis or using other methods known from the prior art which are conventionally used for cleaving specific protecting groups.
Method F
In order to prepare compounds of general formula (I)
B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94Axe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94B xe2x80x83xe2x80x83(I)
wherein B1 and B2 denote xe2x80x94C(xe2x95x90NR1)xe2x80x94NH2 with R1xe2x89xa0H, compounds of general formula (I), wherein B1 and B2 denote xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, are reacted with chloroformates or acyl halides or corresponding anhydrides. For this, the bis-benzamidines in solvents such as toluene, ether, dichloromethane, DMF, ethyl acetate, water at temperatures of 0xc2x0 C. to 120xc2x0 C. are combined with acyl halides or acid anhydrides, with the addition of a basic substance such as triethylamine, cyclic amines such as DBU, or pyridine. The amines may also be used as solvents. Two-phase mixtures such as e.g. water/toluene or water/dichloromethane are also suitable for the reaction.
The compounds of formula (I) wherein B1 and B2 denote xe2x80x94C(xe2x95x90NR1)xe2x80x94NH2 (with R1xe2x89xa0H) may also be prepared from the acylated amidines (IV) and (V) according to Method D and E. In this case the group R1 acts as the protecting group PG. There is no need here to cleave the protecting group PG as mentioned in Method D and E.
Method G
In order to prepare compounds of general formula (I)
xe2x80x83B1xe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94Axe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94B2 xe2x80x83xe2x80x83(I)
wherein B1 and B2 denote xe2x80x94CH2xe2x80x94NH2, the corresponding nitrile compounds of general formula (III)
NCxe2x80x94Ar1xe2x80x94X1xe2x80x94Ar2xe2x80x94X2xe2x80x94Axe2x80x94X3xe2x80x94Ar3xe2x80x94X4xe2x80x94Ar4xe2x80x94CN xe2x80x83xe2x80x83(III)
are reduced, either by catalytic hydrogenation in solvents such as methanol, ethanol, higher alcohols, DMF or water, with catalysts such as Raney nickel, Pd/C, platinum, or with hydride reagents, such as NaBH4, Ca(BH4)2, LiAlH4 and other Alxe2x80x94 or B-hydrides at temperatures of 0-100xc2x0 C. and pressures of 760 Torr or more.
The abovementioned methods A-G are suitable for synthesising both symmetrical and non-symmetrical compounds of general formula (I).
Some methods of preparing the compounds of general formula (I) according to the invention are described in more detail hereinafter, by way of example. The Examples which follow serve only as a detailed illustration, without restricting the subject of the invention.